Mouse Models of Holoprosencephaly

Curr Opin Neurol. 2003 Apr;16(2):135-41. doi: 10.1097/01.wco.0000063761.15877.40.


Purpose of review: Holoprosencephaly (HPE) is the most common anomaly of forebrain development in humans. The pathogenesis of HPE results in a failure of the brain hemispheres to separate during early development. Here we review experimental models of HPE in which some of the genes known to cause HPE in humans have been disrupted in the mouse.

Recent findings: To date, mutations that cause HPE have been identified in seven genes. Three of these genes encode members of the Sonic hedgehog (SHH) signaling pathway, which regulates the development of ventral structures throughout the neuraxis. Two other HPE mutations affect signaling by Nodal ligands, which also play important roles in neural patterning. The roles of the two other known HPE genes are not yet clear. Analysis of genetically altered mice has revealed that mutations in other members of the SHH and Nodal signaling pathways also result in HPE phenotypes.

Summary: Studies of HPE in the mouse have provided a framework for understanding key developmental events in human brain development and may provide new candidate genes for human HPE. Despite this progress, fundamental mysteries remain about how molecules that pattern ventral brain regions ultimately disrupt the formation of the cerebral hemispheres in dorsal regions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Eye Proteins
  • Hedgehog Proteins
  • Holoprosencephaly / genetics*
  • Holoprosencephaly / metabolism*
  • Homeodomain Proteins / metabolism
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Mutation*
  • Nerve Tissue Proteins / metabolism
  • Nodal Protein
  • Nuclear Proteins
  • Prosencephalon / abnormalities
  • Prosencephalon / growth & development
  • Signal Transduction
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism*


  • Eye Proteins
  • Hedgehog Proteins
  • Homeodomain Proteins
  • NODAL protein, human
  • Nerve Tissue Proteins
  • Nodal Protein
  • Nodal protein, mouse
  • Nuclear Proteins
  • Shh protein, mouse
  • Sine oculis homeobox homolog 3 protein
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • ZIC2 protein, human
  • Zic2 protein, mouse